Without limiting the scope of the invention, its background is described in connection with histone deacetylase inhibitors, in particular, structural analogs of compounds related to a histone deacetylase inhibitor known as FK228 or depsipeptide. In the cell, DNA is packaged in the form of chromatin and serves as a dynamic scaffold to regulate various nuclear processes including DNA transcription, replication, repair, mitosis and apoptosis. Chromatin includes 147 base pairs of DNA is wrapped around an octamer of four core histone proteins. Histones are integral and dynamic components of the gene transcriptional machinery and offer a potential regulation points for gene therapy. Specifically, acetylation of specific residues has been associated with active chromatin regions and has been linked to active gene transcription. As such, the histone deacetylase family of enzymes playing an important role in gene expression and have been implicated in cell-cycle arrest and induced differentiation.
For example, the U.S. patent application publication number 20050209134 entitled “novel depsipeptide compound” described a compound which is useful as an agent for prevention and treatment of diseases associated with HDAC, in particular, tumor or cell proliferative diseases. The depsipeptide compound or its pharmaceutically acceptable salt in the '134 application has a good HDAC inhibitory activity and an inhibitory activity of cell proliferation against human cancer cells and, therefore, is useful in treatment and improvement of diseases and pathogenic conditions associated with histone acetylation, in particular, tumor or cell proliferative diseases.
Yet another example can be found in the U.S. patent application publication number 20070129290 that relates to HDAC inhibitor derivatives. The derivatives of the free thiol of metabolites of the HDAC inhibitor FK228, pharmaceutical compositions thereof, and to methods of using such derivatives and pharmaceutical compositions thereof in the treatment of diseases associated with HDAC, in particular, tumor or cell proliferation diseases.
U.S. Pat. No. 7,098,186 teaches a depsipeptide compound which is useful as an agent for prevention and treatment of diseases associated with HDAC, in particular, tumor or cell proliferative diseases. The depsipeptide compound or its pharmaceutically acceptable salt has a good HDAC inhibitory activity and an inhibitory activity of cell proliferation against human cancer cells and, therefore, is useful in treatment and improvement of diseases and pathogenic conditions associated with histone acetylation, in particular, tumor or cell proliferative diseases.
A histone deacetylase inhibitor called as depsipeptide (also known as FK228) is originally isolated from Chromobacterium violaceum, and is an exceptionally potent antitumor agent. However, despite its promising in vivo activity, only limited structure-activity relationship study have been carried out presumably resulting from its synthetic difficulties. Its reported synthesis involved 19 steps with an overall yield of about 18% by highly skilled artisans. Its synthetic difficulties prevented traditional structure-activity study of depsipeptide to discover more potent and selective analogues toward various cancer cell lines. In addition, depsipeptide has been found to be extremely cytotoxic and nonspecific in action with little specificity between normal and tumor cells. These challenges have not been met with any solutions and prevented further attempts of improving its potency, selectivity, and pharmacokinetic profile since its derivatives have not been prepared at all.
Thus, the present inventor recognized that there is a need to design novel structural analogues of FK228 so that a large number of compounds can be produced with high efficiency, and with significantly less side effects while high potency is retained.